A major function of the thyroid gland is to secrete the thyroid hormones L-thyroxine (T4) and L-triiodothyronine (T3). These thyroid hormones regulate important aspects of metabolism. A state of hypothyroidism exists when the blood levels of T3 and T4 are abnormally low, and hyperthyroidism exists when their levels are abnormally elevated. Untreated, severe hypothyroidism is characterized by weight gain, low energy and depression, intolerance of cold, and changes in skin and hair. Untreated, severe hyperthyroidism presents as a state called thyrotoxicosis, characterized by weight loss, nervousness or emotional instability, intolerance of heat, tremor, and a rapid heart rate, and can cause cardiac atrial fibrillation. In some cases hypothyroidism or hyperthyroidism may occur with no discernible symptoms or signs despite abnormal findings on laboratory tests of thyroid function (e.g., a subclinical thyroid disorder).
T3 and T4 are produced under direct control by the anterior pituitary glycoprotein hormone thyrotropin (thyroid stimulating hormone, TSH), which is itself regulated by the hypothalamic hormone thyrotropin releasing hormone (TRH). TSH acts through a membrane-bound G-protein coupled receptor (TSH-R) to activate the major thyroidal functions. Synthesis of T3 and T4 requires incorporation of iodide into their precursor. Thyroid peroxidase (TPO) is a membrane-bound, glycosylated heme-containing enzyme that catalyzes both the iodination of tyrosyl residues and the coupling of iodotyrosyl residues in thyroglobulin to form T3 and T4. Once synthesized, T3 and T4 are stored in a colloidal form on the protein thyroglobulin (Tg) prior to release of the hormones.
Under pathological conditions, the TPO, TSH-R, and Tg proteins may become autoantigens, i.e., targets for autoimmune responses most easily identified by the auto-antibodies that bind these proteins. Historically, antibodies reactive with the microsomal fraction of thyroid tissue were also detected and studied. Later, thyroid peroxidase was found to be the chief target for such anti-thyroid microsomal antibodies. With this understanding, thyroid microsomal antibodies and thyroid peroxidase antibodies have been considered to be essentially equivalent terms.
The signaling function of the TSH-R protein normally becomes activated only upon binding of thyrotropin. However, some antibodies directed against the TSH-R (hereafter, TSHRA) may bind at the thyrotropin docking site, and this class of TSHRA autoantibody can act as a direct agonist (stimulating antibody) or antagonist (blocking antibody) of the TSH-R. Thus, thyroid autoimmunity can be associated with aberrant regulation of thyroid hormone secretion and cause either hypo- or hyper-thyroidism.
A common diagnostic finding in patients with the disorder variously known as Graves' disease, diffuse toxic goiter, von Basedow's disease, or Parry's disease is the presence of TSHRA in the blood. Antibodies directed against TPO (hereafter, TPOA) may be present or absent in Graves' disease. As explained above, patients with this disorder may present clinically with either hypo- or hyper-thyroidism, and a given patient may at different times manifest both conditions. In addition to thyroid dysfunction, the disorder may involve other tissues. In Graves' ophthalmopathy (technically an orbitopathy, because the changes are confined to orbital structures and spare the internal structure of the eye), enlargement of the extraocular muscle bundles and adipose hypertrophy cause protrusion of the eyeball (exophthalmos or proptosis) resulting in double vision (diplopia) and, in severe cases, visual loss. Some patients develop a dermopathy characterized by edema and thickening of the skin, or thickening of the finger bones. Hyperthyroid Grave's disease can often be managed with oral thyroid suppressant drugs, such as methimazole or propylthiouracil. Refractory cases may require thyroid ablation using radioactive iodine or a surgical thyroidectomy. With thyroid suppression, the patient will require thyroid replacement hormone. Severe ophthalmopathy may require radiation therapy delivered to the orbits or surgical decompression of the orbit.
Autoimmune thyroiditis is commonly known among endocrinologists as “silent thyroiditis” and Hashimoto's thyroiditis. TPOA are commonly present in patients with this disorder; high levels of TPOA in the context of the clinical presentation of hypothyroidism is often taken as confirmation for the diagnosis of Hashimoto's disease. TSHRA are usually absent. In this disorder, immune-mediated damage to the thyroid gland may lead to leakage of stored hormone with associated transient thyrotoxicosis, but commonly eventuates in an underactive thyroid gland with associated hypothyroidism. Treatment usually involves thyroid replacement hormone.
Certain disease states or therapeutic interventions are associated with an increased risk for autoimmune thyroid disorders. For example, thyroid disorders occur frequently among patients who receive interferon-alpha therapy for hepatitis C virus infection (Preziati, D., et al., Eur J Endocrinol, 132(5)587-93 (1995)). Among patients with hepatitis C virus infection, pretreatment antibodies to TPO or to thyroid microsomal fraction (a portion of which are known to recognize TPO) appear to be a marker for increased risk of hyper- and hypothyroid disorders among patients who subsequently receive interferon-alpha therapy (Marazuela, M., et al., Clin Endocrinol 44:635-42 (1996); Watanabe, U., et al., Am J Gastroenterol, 89(3):399-403 (1994); Fernandez-Soto, L.,et al., Arch Intern Med, 158:1445-1448 (1998)). Similarly, TPOA detected during pregnancy appear to predict risk for post-partum thyroid disorders (Vargas, M. T., et al., J. Clin. Endocrinol. Metab., 67(2):327-33 (1988)).
Autoimmune thyroid disorders also occur with increased frequency among patients who have previously received lymphocyte depleting therapies. One such therapy is alemtuzumab. Alemtuzumab (Campath®, MabCampath®, Campath-1H®) is a humanized monoclonal antibody that binds selectively with the protein antigen known as CD52. CD52 is an abundant molecule (approximately 5×10^5 antibody binding sites per cell) present on at least 95% of all human peripheral blood lymphocytes and monocytes/macrophages (Hale G, et al., The CAMPATH-1 antigen (CD52). Tissue Antigens;35:178-327 (1990)), but is absent from haemopoietic stem cells. Treatment of a person with alemtuzumab using an appropriate dosage and regimen will, among other effects, result in prompt and relatively sustained depletion from the bodily tissues and blood of normal and neoplastic lymphocytes while sparing the haemopoietic stem cells that are needed to repopulate the immune system. Alemtuzumab is disclosed in U.S. Pat. No. 5,846,534.
Alemtuzumab is approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients who have been treated with alkylating agents and who have failed fludarabine therapy. Clinical studies have shown that alemtuzumab is also active in other hematologic malignancies such as non-Hodgkin's lymphoma and leukemias, and in a variety of immune mediated disorders including graft-versus-host disease, organ transplant rejection, rheumatoid arthritis, and, notably multiple sclerosis (Hale G. and Waldmann H., From laboratory to clinic: the story of CAMPATH-1. In: George A J T, Urch C E, eds. Methods in Molecular Medicine: Diagnostic and Therapeutic Antibodies. NJ: Humana Press; 2000; 40:243-266).
Hale and Waldmann were the first to disclose the use of Campath-1H to treat multiple sclerosis (MS) (see U.S. Pat. No. 6,120,766). Since then, the safety and efficacy of Campath-1H has been the focus of several clinical studies in patients with MS (See, e.g.: T. Moreau et al., Lancet (1994), 344:298-301; T. Moreau et al., Brain (1996), 119:225-237; A. Coles et al., Ann. Neurol. (1999), 46:296-304; A. Coles et al. (Neurology 60 March 2003 (Suppl. 1); A. Coles et al., Clinical Neurology and Neurosurgery (2004), 106:270-274).
Most recently, in the Phase 2 clinical study designated CAMMS223, alemtuzumab was administered at two dose levels (a five day course of 12 mg or 24 mg/day for cumulative doses of 60 or 120 mg in the first year, followed by a three-day course of 12 mg or 24 mg/day for cumulative doses of 36 or 72 mg in the second year, with possible retreatment similarly using 36 or 72 mg in the third year). In an active comparator design, patients on the control arm received interferon beta-1a (Rebif®; EMD Serono, Inc.) 44 mcg subcutaneously (SC) three times per week as indicated in the product label (O'Donnell, L, et al, Presented at the Consortium of Multiple Sclerosis Centers Annual Meeting, Toronto, Canada, Jun. 2-6, 2004; Compston, A., et al., Presented at the 22nd meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Madrid, Spain. Sep. 27 to 30, 2006; Fox, E., et al., Presented at the ECTRIMS, Madrid, Spain (2006)).
Interim results were derived from pre-specified efficacy and safety interim analyses conducted after one or two years of treatment for all patients in the planned three year trial. They showed that alemtuzumab was more effective than interferon beta-1a (Rebif®; EMD Serono, Inc.), a licensed treatment for MS, in reducing the risk of MS relapse and in slowing the accrual of sustained disability. Specifically, patients treated with either alemtuzumab regimen experienced at least a 75% reduction in the risk for relapse after at least one- and two-years of follow-up when compared to patients treated with interferon beta-1a. The alemtuzumab-treated patients additionally experienced at least a 60% reduction (relative to Rebif®-treated patients) in the risk for the sustained accumulation of disability after 1 year, and at least a 65% reduction in that risk after 2 years.
During pilot studies of alemtuzumab as a treatment for MS, it was noted that a high percentage of individuals developed disorders involving the thyroid gland. The first report of this phenomenon (Coles et al. Lancet, 354:1691-95 (1999)) described clinical and laboratory evidence of autoimmune thyroid disease developing in roughly one third of patients (9 of 27) who had previously received alemtuzumab as treatment for their MS. Specifically, these patients had developed antibodies against the thyrotropin receptor and carbimazole-responsive autoimmune hyperthyroidism, and several of them also had episodes characterized as autoimmune thyroiditis. Subsequent studies from the same group (Coles et al., Neurology, 60 March 2003, Suppl. 1) and others (Compston, A., et al., Presented at the 22nd meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Madrid, Spain. Sep. 27 to 30, 2006) have confirmed that thyroid glandular disorders occur with increased frequency following alemtuzumab treatment in patients with MS. Onset of thyroid disorders is typically delayed by several months or years following initial exposure to alemtuzumab.
Delayed onset of thyroid disorders also occurs in other circumstances characterized by lymphocyte depletion and repopulation, notably delayed onset of thyroid disorders following bone marrow transplantation, whether autologous or allogeneic, and whether for treatment of primary immunodeficiency or for reconstitution after iatrogenic bone marrow suppression (Ishiguro H., et al., J Clin Endocrinol Metab, 89(12):5981-6 (2004); Slatter M. A., et al., Bone Marrow Transplant., 33(9):949-53 (2004); Carlson K., et al., Bone Marrow Transplant., 10(2):123-7. (1992); Lee W. Y., et al., Bone Marrow Transplant., 28(1):63-6. (2001)). Chemotherapeutic regimens in these cases varied widely. Their chief similarity with the thyroid-disease prone alemtuzumab-treated MS patients is the regeneration of lymphocyte populations from an initial state of natural or iatrogenic depletion.
A scientific understanding of the pathogenesis of thyroid autoimmune disorders that complicate lymphocyte depleting therapies, and the reason for a delay in onset of these disorders, is currently incomplete.
In summary, alemtuzumab appears to be an effective treatment for patients with a variety of disorders, but its use in MS but has been associated with auto-immune complications including thyroid glandular disorders. Similar complications occur with other lymphocyte depleting therapies. In some individuals, the benefit from therapeutic regimens involving lymphocyte depletion may be offset by adverse effects. Thus, in order to maximize the benefit-to-risk ratio attending the use of a lymphocyte depleting therapy such as alemtuzumab in patients (e.g., MS patients), it would be desirable to have a means for identifying (e.g., prior to the initiation of alemtuzumab treatment) those individuals who are at increased risk for autoimmune thyroid disorders. Such prediction of risk would be useful to support informed medical decision making, e.g., whether or not to initiate treatment with a lymphocyte depleting regimen in a given individual based on the predicted risk for this adverse effect.